von Hippel-Lindau Disease (VHL) To gain insights into the natural history of VHL-associated central nervous system (CNS) hemangioblastomas, we complete a natural history study of 250 VHL patients (Lonser et al. 2014) Analysis of serial clinical and imaging findings in VHL patients revealed that nearly all hemangioblastomas demonstrated a saltatory growth pattern characterized by periods of growth and quiescence. Because of this pattern of growth, many tumors remained unchanged in size for years, asymptomatic, and not requiring treatment. Furthermore, peritumoral cysts were frequently found with CNS hemangioblastomas. The rate of enlargement of these peritumoral cysts was most often far greater than for the hemangioblastoma and, when symptoms appeared, most of the symptom-producing mass effect was from the cyst, not the associated hemangioblastoma. Longitudinal imaging and cyst fluid analyses demonstrated that the mechanism that underlies the formation of peritumoral cysts is plasma extravasation through permeable tumor vessels. Subsequently, factors that lead to increased tumor vessel permeability (e.g., radiation) may exacerbate edema and/or cyst propagation, while targeted therapeutic agents that reduce tumor vascular permeability could potentially reduce edema/cyst formation and delay or prevent symptom development. Previous studies have suggested that a developmentally-arrested hemangioblast is the neoplastic cell of origin of a hemangioblastoma. Characterized and cultured VHL-associated tumor cells from resected CNS hemangioblastomas share the mesodermal markers brachyury, Flk-1, and Scl, with the embryologic hemangioblast. Furthermore, these neoplastic cells with lost heterozygosity of the VHL gene can be expanded and differentiated in culture into blood and endothelial progenitors. Loss of heterozygosity analysis also demonstrated that mast cells in VHL are tumor-derived. These findings indicate that embryologic hemangioblasts are the cells of origin of VHL-associated CNS hemangioblastomas. Treatment strategies targeting the mechanism of tumorigenesis of hemangioblastomas are being developed. New, noninvasive treatments for VHL-associated CNS hemangioblastoma are needed. Our laboratory has documented that mutant VHL protein that results from a germline missense VHL gene mutation retains some biochemical function, but this activity is lost due to accelerated breakdown of the mutant protein. Vorinostat, a histone deacetylase inhibitor that is approved for the treatment of refractory cutaneous T-cell lymphoma (CTCL), has been shown experimentally to slow the intracellular breakdown of the mutant VHL protein. An intramural clinical study (14-N-0067) is ongoing in which vorinostat is given for 1 week to adult patients with known germline missense VHL gene mutation who require surgical resection of a hemangioblastoma. The tumor specimens from surgery are examined for the presence and quantity of mutant VHL protein. Comparisons for levels of mutant VHL protein will be made to tissue banked from previous surgical resections under 03-N-0164. Measurements of genetic expression of vascular endothelial growth factor (VEGF) and erythropoietin (EPO) are also be performed on these specimens. This study will provide preliminary data that may support a subsequent therapeutic clinical trial of vorinostat in patients with VHL and missense VHL mutations. This year Surgical Neurology Branch members continued to publish articles explaining the mechanism of tumor formation in patients with VHL or other tumors with mutation of VHL-related genes, such as hypoxia inducible factors (HIFs). VHL protein targets degradation of HIFs. Loss of VHL function results in intranuclear HIF accumulation, increased expression of VEGF, PDGF, and erythropoietin, tumor angiogenesis, and growth. Mutations that greatly enhance HIF function can produce similar pseudohypoxic effects. Endolymphatic sac tumors (ELSTs) in VHL are frequently associated with hearing loss, tinnitus and vertigo. In VHL, bilateral ELSTs can occur bilaterally and can underlie significant neurologic disability, including binaural deafness. While sporadic and VHL-associated ELSTs can cause devastating audiovestibular dysfunction, the underlying pathophysiologic mechanisms of this dysfunction and the optimal timing of treatment of ELSTs had not been defined. Previously, we analyzed the serial imaging, clinical and surgical findings in VHL patients with ELSTs and found that ELST size was not related to audiovestibular morbidity. Further, it was revealed that ELST-associated audiovestibulopathy is due to tumor-associated intralabyrinthine hemorrhage, or endolymphatic hydrops. These pathophysiologic mechanisms of hearing loss and vestibulopathy can be found with very small tumors. These findings suggest that the frequent finding of unexplained VHL-associated audiovestibular dysfunction may in part be explained microscopic ELSTs. Because audiovestibular morbidity is not related to tumor size and is unpredictable, early detection via improved testing/imaging and surgical treatment of ELSTs can reduce audiovestibular morbidity. Neurofibromatosis Type 2 (NF2) The protean nature of central nervous system tumors in NF2 and incomplete understanding of their natural history and underlying mechanisms of symptom formation have resulted in treatment being delayed until after the development of neurologic deficits. Based on this treatment paradigm, tumors at the time of treatment are typically large and associated with irreversible neurologic deficits and increased risk of treatment-induced morbidity. Subsequently, knowledge of the natural history of tumors associated with NF2 is critical in predicting the future growth of a tumor and deciding on the best treatment of affected patients. To gain clinical and molecular insights into the effects of NF-2 gene mutations on tumor development/progression and to identify features associated with symptom evolution in NF2-associated tumors, we are performing an ongoing natural history study of NF2 patients. Eighty-six (86) patients have completed the study by reaching the prescribed 5-year follow-up time point. We will continue to follow all enrolled patients until the end of their 5-year time points (will take us to the end of year 2018). We are accruing data which will permit us to gain a better understanding of the natural history of CNS tumors in NF2. So far, variable patterns of tumor growth, including novel patterns such as a stuttering pattern of tumor growth, have been identified within many subjects. Preliminary studies suggest that genetic factors beyond the NF2 gene mutation can promote increased meningioma aggressiveness in patients with NF2. This prospective natural history study should be useful in identifying the factors that determine tumor biology and behavior as it relates to symptom formation and ultimately, optimal treatment timing.